Combination preparation of estrogen and anti-estrogen

Details Combination preparation of estrogen and anti-estrogen Combination preparation of estrogen and anti-estrogen

2000-08-21

2004-01-13

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

Reexamination Certificate

active

06677324

ABSTRACT:

This application is a 371 of FCT/EP99/01023 filed Feb. 18, 1999.
The invention relates to a combination preparation of an oestrogen and an antioestrogen. Owing to the decreasing production of oestrogen, during the change of life and after the menopause acute symptoms needing treatment, such as hot flushes, suddenly occurring outbreaks of sweating, racing heart and other vasomotor symptoms occur in many women. The loss of the endogenous oestrogens can lead in the long term to an increased loss of bone mass (osteoporosis) and to an increase in cardiovascular disorders. More recent epidemiological investigations have shown that physiological and pathological ageing symptoms of the central nervous system are partially to be attributed to the loss of oestrogen. Examples of these which may be mentioned are limitations of the memory power of the short-term memory (S. M. Phillips, B. B. Sherwin, 1992, Psychoneuroendocrinology 17, 485) and Alzheimer's disease (A. Paganini-Hill, V. W. Henderson, 1994, Am. J. Epidemiol. 140, 256).
Hormone replacement therapy has the aim of substituting the losses of the endogenous oestrogens commencing with the menopause and thus preventing both the acute and the long-term symptoms. Today the therapy is either carried out as oestrogen monotherapy or as combination therapy with gestagens. A disadvantage of the monotherapy is the proliferative action of the oestrogen on the endometrium, which can lead to endometrial hyperplasia and adenocarcinomas. With combination therapy, withdrawal bleeding or intracyclic menstrual bleeding occurs, which markedly restricts the acceptance of the therapy and frequently leads to the discontinuance of the therapy. Furthermore, adverse effects of the gestagens on the cardioprotective and positive central actions of the oestrogens are discussed.
A further possibility for hormone substitution is the combination of an oestrogen with an antioestrogen. In this case, the protective effects of the oestrogen in the bone should be retained, while the undesired effects on the endometrium should be antagonized (EP 0346014). It is, however, disadvantageous when the antioestrogen reaches the central nervous system and antagonizes the positive properties of oestrogen there. It is reported, for example, for tamoxifen that it induces typical, acute climacteric symptoms such as hot flushes (S. Litherland, M. Jackson, 1987, Cancer Treat Revs. 15, 183). It. was possible to show that the substance reaches the central nervous system and acts there as an oestroaenic antagonist (A. Biegon et al., 1996, Cancer Research 56, 4328). It would also not be desirable if the antioestrogen were to counteract the protective action of the oestrogen in Alzheimer's disease.
The technical problem then lies in finding a combination preparation of an oestrogen and an antioestrogen in which the antioestrogenic component does not reach the central nervous system and simultaneously has an antiproliferative action on the endometrium.
The problem is now solved in that a combination preparation has been found in which the oestrogen is selected from the group consisting of 17-&bgr;-oestradiol, 17-&agr;-ethynyloestradiol, oestriol, oestrone, oestrone sulphate, oestrogen sulphamates, 17&agr;-oestradiol, mestranol, stilboestrol, esters of 17&bgr;-oestradiol, such as, for example, oestradiol valerate and naturally conjugated oestrogens and in that the antioestrogen is a substituted 7&agr;-(&xgr;-aminoalkyl)oestratriene of the general formula I
in which
the side chain SK is a radical of the subformula
where m is 4, 5 or 6,
n is 0, 1 or 2,
x is 0, 1 or 2,
A is a hydrogen atom or a C
1-5
-alkyl group,
B and D are each a hydrogen atom, or
A and B together are an alkylene group —(CH
2
)
p
— with p=2, 3, 4 or 5 and D is a hydrogen atom or
A and D together are an alkylene group —(CH
2
)
q
— with q=2, 3 or 4 and B is a hydrogen atom, and
E is an unsubstituted or mono- to pentafluorinated ethyl radical, or the terminal substituent —(CH
2
)
3
—E in the side chain is replaced by an optionally substituted aryl or heteroaryl radical which is bonded to the sulphur atoms directly or via a mono-, di- or trimethylene group,
R
3
is a hydrogen atom, a hydrocarbon radical having up to 8 carbon atoms or a radical of the subformula R
3′
—C(O)—, in which R is a hydrogen atom or a hydrocarbon radical having up to 8 carbon atoms or a phenyl radical,
R
11
is a hydrogen atom, a halogen atom or a nitrooxy group —O—NO
2
,
R
14
, R
15&agr;
, R
15&bgr;
, R
16&agr;
and R
16&bgr;
are each a hydrogen atom or
R
14
and R15&agr; are an additional bond or a methylene bridge, or
R
15&bgr;
is a methyl group and R
15&agr;
is a hydrogen atom, or
R
15&agr;
and R
15&bgr;
are each a methyl group, or
R
15&bgr;
and R
16&bgr;
together are a methylene bridge, or
R
16&agr;
or R
16&bgr;
is a halogen atom or
R
16&agr;
and R
16&bgr;
together are a methylidene group and the remaining substituents R
14
, R
15&agr;
, R
15&bgr;
, R
16&agr;
and
R
16&bgr;
are each a hydrogen atom,
R
17′
in the &agr;- or &bgr;-position is a hydrogen atom, a C
1-5
-alkyl, C
2-5
-alkenyl or C
2-5
-alkynyl group or a trifluoromethyl group and
R
17″
is a hydrogen atom or a radical of the subformula R
17′″
—C(O)—, in which R
17′″
is a hydrogen atom or a hydrocarbon radical having up to 8 carbon atoms, or, if R
17′
is located in the &agr;-position, R
17′
together with R
14
is an ethano bridge,
with the proviso that, if A and B together are not —(CH
2
)
p
— or A and D together are not —(CH
2
)
q
—, at least one of: the substituents R
11
, R
14
, R
15&agr;
, R
15&bgr;
, R
16&agr;
and R
16&bgr;
and R
16&bgr;
is not a hydrogen atom,
and their physiologically tolerable addition salts with organic and inorganic acids.
Moreover, a combination preparation is made available in which the oestrogen is selected from the group consisting of 17-&bgr;-oestradiol, 17-&agr;-ethynyloestradiol, oestriol, oestrone, oestrone sulphate, oestrogen sulphamates, 17&agr;-oestradiol, mestranol, stilboestrol, esters of 17&bgr;-oestradiol, such as, for example, oestradiol valerate and natural conjugated oestrogens and the antioestrogen is an 11&bgr;-halo-7&agr;-substituted oestratriene of the general formula II
in which
R
3
is a hydrogen atom, a hydrocarbon radical having up to 8 carbon atoms or a radical of the subformula R
3′
—C(O)—, in which R
3′
is a hydrogen atom or a hydrocarbon radical having up to 8 carbon atoms or a phenyl radical,
R
7
is a radical of the formula —A—B—Z—R
20
, in which
A is a direct bond or a benzylidene radical, where the methylene group is bonded to the 7-carbon atom of the steroid, or a phenylene radical,
B is a straight- or branched-chain alkylene, alkenylene or alkynylene group having 3 to 14 carbon atoms, and
Z is —NR
21
— and R
21
is a C
1
-C
3
-alkyl group, where R
20
then is
a hydrogen atom,
a straight- or branched-chain alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, or one of the groups
—D—C
n
F
2n−1
, where D is a straight- or branched-chain alkylene, alkenylene or alkynylene group having up to 8 carbon atoms and n is an integer from 1 to 8,
—L—CH═CF—C
p
F
2p+1
, where L is a straight- or branched-chain alkylene, alkenylene or alkynylene group having 2 to 7 carbon atoms and p is an integer from 2 to 7,
—D—O—(CH
2
)
q
-aryl, where D has the meaning already indicated, q is 0, 1, 2 or 3 and aryl is an optionally mono- or disubstituted phenyl radical, 1- or 2-naphthyl radical or a heteroaryl radical,
—D—O—(CH
2
)
r
—C
n
F
2n+1
, where D and n have the meanings already indicated and r is an integer from 1 to 5, or
R
20
and R
21
with the nitrogen atom to which they are bonded form a saturated or unsaturated heterocycle having 5 or 6 chain members, which optionally contains one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and is optionally substituted, or
Z is —SO
x
— and x is 0, 1 or 2, where R
20
then is
a straight- or branched-chain alkyl, alkenyl or alkynyl group ha

Affiliated with

Also associated with

Rating

Combination preparation of estrogen and anti-estrogen does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Combination preparation of estrogen and anti-estrogen, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Combination preparation of estrogen and anti-estrogen will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3255817